The ability to detect and identify genetic sequence polymorphisms will become increasingly important in diagnosing human disease and disease tendencies and cataloguing human genetic variations over the coming decade. The research proposed is aimed at study of a conceptually new topology-based approach to identification of specific DNA and RNA sequences both in vitro and in tissue samples. This approach involves the use of modified DNA probes that can self-ligate to circular form in the presence of other topologically closed DNAs. This process requires no enzymes, and results in cascade reactions that can give amplified signals for detection. In principle, these new strategies avoid the need for isolation or PCR-based amplification of the target nucleic acids. The specific aims of this work include: 1) testing the effects of template size and complementarity on the topology of the products; 2) characterizing topologically linked products and polymers; 3) testing the specificity of the cascade initiation; and 4) application of these cascade reactions to detection of genetic targets. If successful, the methods will allow the discrimination of even single-base differences in nucleic acids simply by examining cells under a microscope, and may also allow the imaging of mutated cells in a larger tissue specimen. They will also allow for enzyme-free identification of DNA and RNA sequences in standard diagnostic formats with high sequence specificity. Over the long term, it is hoped that this approach will give rise to clinically useful methods for the early diagnosis of diseases.